1. Field of the Invention
The present invention relates generally to the use of compounds to treat a variety of disorders, diseases and pathologic conditions and more specifically to the use of Hedgehog antagonists for inhibiting hedgehog pathway activity in hematopoietic cell cancer.
2. Background Information
Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the mechanisms underlying these patterning effects usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families.
Members of the Hedgehog family of signaling molecules mediate many important short- and long-range patterning processes during invertebrate and vertebrate development. Exemplary hedgehog genes and proteins are described in PCT publications WO 95/18856 and WO 96/17924. The vertebrate family of hedgehog genes includes at least four members, three of which, herein referred to as Desert hedgehog (Dhh), Sonic hedgehog (Shh) and Indian hedgehog (Ihh), apparently exist in all vertebrates, including fish, birds, and mammals. A fourth member, herein referred to as tiggie-winkle hedgehog (Thh), appears specific to fish. Desert hedgehog (Dhh) is expressed principally in the testes, both in mouse embryonic development and in the adult rodent and human; Indian hedgehog (Ihh) is involved in bone development during embryogenesis and in bone formation in the adult; and, Shh is primarily involved in morphogenic and neuroinductive activities. Given the critical inductive roles of hedgehog polypeptides in the development and maintenance of vertebrate organs, the identification of hedgehog interacting proteins and their role in the regulation of gene families known to be involved in cell signaling and intercellular communication provides a possible mechanism of tumor suppression.
Hematopoietic malignancies are frequently associated with chromosomal translocations, inversions and deletions. These genetic events may lead to the aberrant expression/activation of a proto-oncogene, to the generation of an oncogenic fusion gene, or to the deletion/inactivation of a tumor suppressor gene. Mutations of oncogenes and tumor suppressor genes have also been implicated in tumorigenesis of the hematopoietic tissue.
Evidence for a critical role of continuous Hh pathway activity in cancer growth comes from the ability of cyclopamine, a potent antagonist of the Hedgehog (Hh) signaling pathway, to inhibit cancer growth in animal models of malignancies arising in tissues such as lung, pancreas, biliary tract, prostate, skin, and brain. Thus, for example, it was observed that complete and durable cyclopamine-induced regression of aggressive prostate cancer xenografts and inhibition of prostate cancer metastasis in athymic mice, all without obvious adverse side effects.
The role of Hh pathway activity in promoting metastatic growth suggests that pathway antagonists may offer significant therapeutic improvements in the treatment of advanced prostate cancer. The ability to modulate one or more genes that are part of the hedgehog signaling cascade thus represents a possible therapeutic approach to several clinically significant cancers. A need therefore exists for methods and compounds that inhibit signal transduction activity by modulating activation of a hedgehog, patched, or smoothened-mediated signal transduction pathway, such as the Hedgehog signaling pathway, to reverse or control aberrant growth related to hematopoietic cell cancer.